Targeting mitochondrial dysfunction and oxidative stress in heart failure: Challenges and opportunities

Abstract

Mitochondrial dysfunction characterized by impaired bioenergetics, oxidative stress and aldehydic load is a hallmark of heart failure. Recently, different research groups have provided evidence that selective activation of mitochondrial detoxifying systems that counteract excessive accumulation of ROS, RNS and reactive aldehydes is sufficient to stop cardiac degeneration upon chronic stress, such as heart failure. Therefore, pharmacological and non-pharmacological approaches targeting mitochondria detoxification may play a critical role in the prevention or treatment of heart failure. In this review we discuss the most recent findings on the central role of mitochondrial dysfunction, oxidative stress and aldehydic load in heart failure, highlighting the most recent preclinical and clinical studies using mitochondria-targeted molecules and exercise training as effective tools against heart failure.

Keywords: Aldehydes; Cardiovascular diseases; Exercise training; Mitochondria; Redox imbalance; Therapy.

Figure 1.

Proposed model for the sources of reactive oxygen species (ROS) in heart failure based on previous studies [38,57,232], which focused in the interplay between defective Ca²⁺ handling and NAD(P)H/NAD(P)⁺ redox state in mitochondrial ROS generation. In green boxes, the pharmacological therapies listed in Table 1. IDPm, mitochondrial NADP+ dependent isocitrate dehydrogenase; MEP, malic enzyme; Nnt, nicotinamide nucleotide transhydrogenase; GR, glutathione reductase; TR, thioredoxin reductase; MCU, mitochondrial Ca2+ Uniporter; Mn-SOD, Mn2+ dependent superoxide dismutase; PRX, peroxiredoxin; GPX, glutathione peroxidase; TRXr/o, reduced/oxidized thioredoxin; GSH/GSSG, reduced/oxidized glutathione; α-KG, α-ketoglutarate; mNCE, Na+/Ca2+ exchanger; MPT, mitochondrial permeability transition.

Figure 2.

Proposed model for the aldehydic overload in heart failure and for the role of aldehyde dehydrogenase 2 (ALDH2) in cardiac diseases. In the first scheme, during the progression of post-MI cardiomyopathy, excessive ROS production (free radicals) leads to lipid oxidation and 4-HNE generation and accumulation. The aldehyde inhibits (1) the proteasome [11,233], (2) the electron transport chain [162,234,235], (3) ALDH2, among other intracellular targets [236]. (4) Pharmacological activation of ALDH2 by Alda-1 improves cardiac outcome and 4-HNE removal [162,163,237]. The second scheme summarizes data from preclinical studies using either ALDH2 transgenic mice or pharmacological ALDH2 inhibitors or activators that elucidated the potential pathways regulated by ALDH2 and aldehydic load in cardiac diseases, including heart failure. Activation of ALDH2 or ALDH2 overexpression confer cardiac protection by counteracting aldehydic load, mitochondrial dysfunction, oxidative stress, impaired contractility and death in failing hearts, whereas inactivating mutation in ALDH2 or the use of selective inhibitors of the enzyme, exacerbate all the disease. This figure was produced using Servier Medical Art templates, which are licensed under a Creative Commons Attribution 3.0 Unported License (https://smart.servier.com).